KIRs comprise a family of inhibitory and activating MHC class I-specific receptors. Differential expression of KIR by NK cells and some T cells creates KIR repertoires that can influence cellular response. KIR are thus implicated in innate and adaptive immunity, and, through NK-cell crosstalk with dendritic cells, in the switch between the two. Human KIR exhibit polymorphism that individualizes NK-cell repertoires. Variables include gene number, ratio of activating and inhibitory KIR, and allelic polymorphism. KIRs represent a rapidly changing component of the human immune system, as seen from the variation between ethnic populations. Such characteristics suggest KIR differences influence human immunity, a hypothesis supported by several preliminary reports of KIR associations with infection, autoimmunity and transplantation. KIR are much more complicated than first anticipated. Consequently, immunological investigation has been limited to KIRs present in Caucasian populations, while population and clinical studies have used analytical methods of low resolution. The overall goals of this renewal application are twofold: first, to obtain an accurate and clear picture of the scope of KIR diversity in the human species and of the events leading to the birth and death of KIR; second, to develop better methods for analyzing KIR haplotypes and genotypes, methods that will facilitate high resolution population analysis and future clinical studies. The four Specific Aims will extend ongoing and productive investigation using established methods, at the same time as new methods are being developed and introduced. Aim 1 will give detailed description of KIR in a human population having a reduced KIR diversity, the Japanese. Aim 2 will define new KIR in Africans, African-Americans and Asian- Indians, poorly studied populations for which much undiscovered diversity is indicated. Already identified is a novel KIR3DL gene (KIR3DL1/2v), common in Africans. KIR3DL1/2v-containing haplotypes will be analyzed in Aim 3 to determine if KIR3DL1/2v is parent or child of the familiar KIR3DL1 and KIR3DL2 genes. To do this, a novel approach for the isolation and analysis of KIR haplotypes will be implemented. This approach will also contribute to Aims 1 and 4; in the latter, typing for KIR haplotypes based upon single nucleotide polymorphisms (SNPs) will be developed. The approach will be piloted in the relatively simple Japanese KIR system and then extended to the more complex and highly mixed population of the US.